Liquid matrix undergoing phase transfer in vivo and liquid oral preparations

ABSTRACT

It is intended to provide a liquid matrix for medicinal use in which medicine can be easily solubilized, dispersed or suspended and which can be easily swallowed because of being liquid, has favorable working properties in sterilization and so on and a high stability, also exhibits an effect of masking bitterness, and gels in vivo so as to control the release speed of the medicine, and liquid oral preparations using the same. Namely, a liquid matrix which is a liquid assistant for facilitating swallowing medicine characterized in comprising a water-soluble polymer gelling under acidic conditions, and the breaking stress of the gel is about 3.00×10 3  N/m 2  or more. Liquid oral preparations have favorable slow release properties even though being a liquid.

TECHNICAL FIELD

The present invention relates to a liquid matrix capable of regulatingthe release of medicine by phase transition from liquid to gel in livingbody, and an oral liquid preparation comprising the liquid matrix andmedicine. That is, the present invention relates to a liquid matrixcapable of oral administration, which can gel in stomach to exhibit aregulatory action on the rate of release of medicine.

Further, the present invention relates to a method of using an aqueoussolution of a water-soluble polymer gelling under acidic conditions, asa component in a sustained-release oral liquid preparation.

BACKGROUND ART

Generally, medicines are administered mainly via oral, and the form ofthe preparations including such medicines is mainly solid preparationsuch as powder, granule, pill, tablet and capsule.

However, easily administrable liquid preparations are preferable forinfants and the elderly originally having difficulty in administrationof pharmaceuticals via oral, or for patients with difficulty inswallowing of pharmaceuticals because of aging and diseases such as anaftereffect of cerebral apoplexy, cerebral contusion attributable toexternal injuries, cerebral palsy and Parkinson's disease.

In consideration of side effects of medicines or the like, a drugdelivery system has been extensively developed in recent years as atechnique of releasing medicines at desired site (small intestine,affected areas and the like). That is, the composition of a preparationis devised so as to permit the preparation to be digested in digestivetracts thereby regulating the rate of disintegration of the preparationto regulate the rate of release of the medicine. For example, JapaneseUnexamined Patent Publication No. Hei 8-231435 discloses biodegradablepolymeric hydrogel which releases medicines depending on biodegradation.

However, there is none of technology on liquid preparations which canregulate the rate of release of medicines. That is, solid preparationsare digested generally in digestive tracts, whereby the rate ofdisintegration of the preparations can be utilized to regulate the rateof release of medicines. On the other hand, liquid preparations couldnot regulate the rate of release of medicines because the medicines arepreviously subjected to solubilization or the like.

For example, a pharmaceutical preparation described in JapaneseUnexamined Patent Publication No. Hei 8-231435 comprises a water-solublepolymer as an essential component for regulating the release of medicinein the living body, but the preparation is in gel form so that it is noteasily ingested by patients having difficulty in swallowing.

On the other hand, the oral administration of liquid preparations is themost effective administration method for infants, the elderly orpatients with difficulty in swallowing, or for patients who should takea large dose of medicines. However, liquid preparations do not exhibitsustained release of medicines. Therefore, their efficacy cannot besustained, and the frequency of administration cannot be reduced.Further, the liquid preparations often cause side effects because ofgood absorption of medicines and rapid increase in the concentration ofmedicines in blood. Accordingly, if these problems inherent in theliquid preparations can be solved, there can be brought aboutimprovements in therapeutic effects such as reduction in the frequencyof administration and reduction in side effects in addition to theirinherently easy administration, thus improving the compliance ofpatients to achieve many medical advantages.

A large number of medicines are sparingly soluble or poor in stabilityupon solubilization, and have an essential problem in adding into liquidpreparations. If bitter tastes of medicines and the like can be masked,resistance to administration of medicines into infants would be reduced.

Japanese Unexamined Patent Publication No. Hei 8-99885 discloses anaqueous acid-regulating composition having stable viscosity, whichcomprises acid-regulating agent, alginate and optionally magnesiumcarbonate. This composition is a gel (magnesium alginate and the like)originally having a predetermined viscosity so that swallowing thereofis not necessarily easy. Further, the gel material is separated into geland water at high pressure or high temperatures thus makingsterilization difficult, which results in a serious disadvantage inproduction of preparations.

A pharmaceutical preparation containing an acid-neutralizing agent(acid-regulating substance) such as an alkaline earth metal is alsodisclosed in Japanese Patent No. 2710375. This pharmaceuticalpreparation comprises pectin capable of forming coagulated gel underacidic pH, buffer and acid-neutralizing agent to form a floating raft inthe stomach. By forming the raft under the acidic environment in thestomach, it is attempted to sustain efficacy and prevent the contents inthe stomach from regurgitating into the esophagus. Japanese ExaminedPatent Publication No. SHO 46-21672 also discloses a compositioncomprising an acid-regulating agent and a gelling agent, and it is alsoattempted to sustain efficacy.

However, these prior art preparations contain a large amount of acidregulating substance, and thus the inside of the stomach is neutralizedto make formation of a gel of sufficient strength impossible, thusmaking duration of efficacy insufficient. In addition, the preparationshould be taken in a large amount, and thus it is difficult to obtainthe compliance of patients in administration. When diseases such asdamaged mucous membrane in the stomach advance to stomach ulcer and thelike, administration of only the acid-regulating agent does notconstitute fundamental treatment, and thus there is a problem that thepreparation fails to serve as a therapeutic agent for stomach ulcer.

In recent years, a microorganism designated as Helicobacter pylori wasisolated from mucous membrane in human stomach. It was revealed thatthis microorganism is a factor causing at least 80% gastritis, and is amajor cause for reoccurrence of digestive ulcers, particularly duodenalulcer. Further, it is being revealed that when infection withHelicobacter pylori is continued, contraction of stomach mucous membraneproceeds while epithelial metaplasia occurs, which leads to stomachcancer.

Accordingly, eradication of Helicobacter pylori (referred to hereinafteras “H. pylori”) constitutes a fundamental treatment of gastritis,stomach ulcer, or the like. Therefore FDA in the US in 1995 recommendederadication therapy of H. pylori by using a macrolide antibiotic i.e.clarithromycin in combination with a stomach acid secretion inhibitori.e. omeprazole or ranitidine bismuth. Five years later, that is, inSeptember 2000, administration of three medicines i.e. a proton pumpinhibitor lansoprazole combined with two antibiotics i.e. lactam-basedamoxicillin and macrolide-based clarithromycin was approved in Japan aseradication therapy of H. pylori infection in stomach/duodenal ulcer.Thereafter, therapy with three medicines using the above-mentionedomeprazole was also approved in February 2002, and the eradicationtherapy of H. pylori is spreading as fundamental therapy for a largenumber of lesions such as duodenitis, erosion, erosive duodenitis anddigestive ulcer.

However, antibiotics used against H. pylori are unstable to stronglyacidic conditions, thus making administration in a larger amountinevitable to compensate for their antibacterial activity. On the otherhand, administration of antibiotics in a larger amount easily causesside effects. Accordingly, it is important for eradication therapy of H.pylori that a proton pump inhibitor be used in combination withantibiotics thereby decreasing secretion of stomach acid to improve thedegree of utilization of the antibiotics.

However, this proton pump inhibitor causes side effects such asdisturbance attributable to reduction in the ability to secrete stomachacid, propagation of bacteria in the stomach, expansion of the stomachafter administration, and generation of reflux esophagitis attributableto rapid secretion of stomach acid due to rebounding. Nevertheless, theamount of proton pump inhibitor used in eradication therapy of H. pyloriis as twice as that usually used. Further, the presence of several % ofpatients for whom the proton pump inhibitor is not effective is anobstacle to use of the eradication therapy.

For stomach/duodenal ulcer, not only eradiation therapy of H. pylori butalso therapy of the ulcer itself is carried out. However, conventionaltherapeutic agents for ulcer are those acting on ulcerous epithelialcells in mucous membrane in the stomach after they are orally ingested,absorbed from digestive tracts, carried via a portal vein into the liverwhere they are metabolized, and delivered with blood to the affectedarea. Therefore, they do not exert their therapeutic effect directly onthe affected area. Accordingly, the effectiveness of the medicines islowered, and the problem of side effects cannot be solved.

As described above, a gel preparation in consideration ofmedicine-releasability and a pharmaceutical preparation gelling in thestomach are known. However, there is no pharmaceutical preparation inliquid form exhibiting sustained release of medicines.

As a therapeutic method for infection with H. pylori regarded as causinggastritis or the like, a method that does not involves administering aproton pump inhibitor capable of causing severe side effects has beendesired. Further, a method of treating stomach ulcer and duodenal ulcerat high level with fewer side effects has also been desired.

In view of the above, an object of the present invention is to provide aliquid matrix as a liquid pharmaceutical assistant for swallowing, whichcan easily solubilize, disperse or suspend medicine, is liquid to permiteasy swallowing, is easily and highly operative in sterilization and thelike, has an effect of masking bitter tastes of medicines and the like,and can gel in the living body to regulate the rate of release ofmedicines.

Another object of the present invention is to provide a liquidpreparation utilizing the liquid matrix, particularly a liquidpreparation effective against H. pylori for which a more excellenteradication method has been desired, as well as a liquid preparationhaving a therapeutic effect on stomach ulcer and duodenal ulcer.

DISCLOSURE OF THE INVENTION

To solve the problem, the present inventors made extensive study onconstituent components of pharmaceutical preparations, and found thatthe problem can be solved by utilizing a water-soluble polymer gellingunder acidic conditions and simultaneously prescribing the breakingstress suitably after gelling, and the present invention was therebycompleted.

The liquid matrix of the present invention is a liquid assistant forfacilitating swallowing medicine, is characterized in comprising awater-soluble polymer gelling under acidic conditions, and the breakingstress of the gel is about 3.00×10² N/m² or more (preferably 2.00×10³N/m² or more). Though the pharmaceutical preparation thus constituted isin liquid form, the preparation can exhibit sustained release ofmedicine by phase transition in the stomach after administration.

The viscosity of the liquid matrix before gelling is preferably 3.0×10⁻¹Pa.s or less (more preferably about 1.0×10⁻¹ Pa.s or less). Because theviscosity of the preparation is low, it can be administered to patientswithout difficulty in swallowing, to reduce their sufferings, and thusthe compliance of the patients can be easily obtained.

Preferably, the liquid matrix of the present invention comprises aninsoluble salt releasing polyvalent metallic cation under acidicconditions, and the insoluble salt is preferably alkaline earth metalsalt of inorganic acid. Preferably, the water-soluble polymer containedin the liquid matrix has carboxyl group and/or sulfonic acid group(which may include both carboxylic acid and sulfonic acid group) in thechemical structure thereof, and specifically alginate, pectin, thecombination of alginic acid or alginate and pectin, gellan gum, or thecombination of gellan gum and pectin is preferable. By using thesewater-soluble polymers, a gel having breaking stress higher than apredetermined value can thereby be reliably formed in the stomach toachieve excellent sustained release of medicine.

The oral liquid preparation according to the present invention ischaracterized in comprising the liquid matrix and medicine, and has thecharacteristics of the liquid matrix. That is, the preparation ischaracterized in that it can be swallowed easily due to liquid and bymasking of the bitter taste of the medicine, and gels in the stomach toexhibit sustained release of the medicine.

The medicine is preferably the one showing an anti-H. pylori activity.Unlike the conventional therapeutic method of eradicating H. pylori, theoral liquid preparation of the invention does not necessitate protonpump inhibitor, and can reduce the amount of antibiotics which should beadministered in the prior art in a larger amount and easily leads sideeffects, while this oral liquid preparation can sustain thepharmacological effect of the medicine.

Such medicine showing anti-H.pylori activity includes at least onemember selected from the group consisting of penicillin antibiotics,macrolide antibiotics, tetracycline antibiotics, cepham antibiotics, andpyridonecarboxylic acid synthetic antibacterial agents. Further, atleast one member selected from the group consisting of amoxicillin,clarithromycin, roxithromycin, minocycline hydrochloride, cephaclor,cephalexin, ofloxacin, tosufloxacin tosylate, and levofloxacin can beexemplified. Though these medicines exhibit high anti-H.pylori activity,they are unstable to strongly acidic conditions, and thus fail toexhibit their antibacterial activity efficiently by the conventionaladministration method. Given an oral liquid preparation utilizing theliquid matrix according to the present invention, however, the amount ofthese medicines to administer can be reduced to such a range that sideeffects are not exhibited, and the antibacterial activity can beexhibited.

The oral liquid preparation has the sustained release of the medicine,that is, the most distinctive feature of the liquid matrix of thepresent invention, and is significantly superior in this feature toconventional liquid preparations.

The medicines are preferably those having a therapeutic effect onstomach ulcer or duodenal ulcer. According to liquid preparations havingsuch medicine, the therapeutic effect is high and side effects can bereduced, because the medicine can be sustainedly released to actdirectly on the affected area in addition to an affected area can becovered and protected with the gel by transformation of the liquidmatrix to gel in the stomach. In treatment of duodenal ulcer, the liquidpreparation of the present invention having gelled in the pyloricvestibule of the stomach can sustainedly release the medicine to permitit to act sufficiently from the pyloric region to the duodenum. Further,an affected area of the duodenum is covered with the gel preparationafter gradual transfer to the duodenum by peristalsis, and the medicineis sustainedly released to the affected area. Accordingly, the liquidpreparation is very useful as a therapeutic agent for stomach ulcer andduodenal ulcer.

The medicines having a therapeutic effect on stomach ulcer or duodenalulcer are preferably those having effect of promoting protection factor.This is because experiments described later have revealed that in theliquid preparation utilizing the liquid matrix according to the presentinvention, medicines of protection factor promoting type have a highertherapeutic effect.

The medicines having an effect of promoting protection factor arepreferably prostaglandin or derivatives thereof. This is becauseprostaglandin and derivatives thereof have an effect of increasing ablood stream in mucous membrane and a promoting effect on the ability tosecrete viscous fluid, and have actual results as remedies for stomachulcer and duodenal ulcer.

The oral liquid preparation comprises the liquid matrix of the presentinvention as a component, and thus naturally has an ability to releasemedicines sustainedly, and in this respect, this preparation issignificantly superior to the conventional liquid preparations.

The method according to the present invention is characterized in thatan aqueous solution of a water-soluble polymer gelling under acidicconditions is used as a component in the sustained-release oral liquidpreparation. The method of the invention also has the characteristics ofthe liquid matrix of the invention.

The most distinctive feature of the liquid matrix according to thepresent invention is that it is liquid in an ordinary state, and thus arelatively large amount of medicine may be added to the matrix, and theliquid matrix can be easily swallowed, while after oral administration,it can gel in the stomach to achieve sustained release of the medicine,and its efficacy can be maintained. That is, when the liquid matrixaccording to the present invention enters in liquid form through theesophagus into the stomach, the water-soluble polymer as one componentgels by the strong acidity of stomach acid.

Unlike the conventional liquid preparation which is sent immediately tothe small intestine where the medicine as an active ingredient isabsorbed, upon reaching the stomach, so that the blood concentration ofthe medicine is rapidly increased and then rapidly decreased, the oralliquid preparation according to the present invention is sent graduallyto the small intestine by peristalsis of the stomach, whereby themedicine is continuously absorbed and the efficacy is exhibitedcontinuously.

Hereinafter, embodiments of the present invention exhibiting suchcharacteristics, and the effect thereof, are described.

The “water-soluble polymer gelling under acidic conditions” is notparticularly limited insofar as it is pharmacologically acceptable andgels with stomach acid. The polymer can be exemplified by alginic acidor a salt thereof, pectin, gellan gum or a combination thereof. Awater-soluble polymer which does not gel by themselves under acidicconditions, but gels under acidic conditions when used in combinationwith gellan gum and the like, can also be used. Such water-solublepolymer includes arabic gum, carrageenan, tamarind seed gum, guar gum,xanthane gum, curdlan, hyaluronic acid and locust bean gum. Thecombination thereof is preferably a combination of gellan gum andpectin, carrageenan or locust bean gum. A combination of alginic acid ora salt thereof and locust bean gum is also preferable.

For forming a gel of high physical strength to exhibit excellentsustained release, the water-soluble polymer is preferably crosslinkedwith polyvalent metallic cations. The water-soluble polymer used thereinis not particularly limited insofar as it is water-soluble in anordinary state and gels upon addition of polyvalent metallic cations,and the water-soluble polymer should be pharmacologically acceptable.Such water-soluble polymer includes, for example, alginates such assodium alginate and propylene glycol alginate; vinyl polymers such ascarboxyvinyl polymer, sodium polyacrylate and polyvinyl alcohol;cellulose derivatives such as carboxymethyl cellulose gum, carboxymethylcellulose and carboxyethyl cellulose; plant polysaccharides such askonjak mannan, pectin, carrageenan and guar gum; microbialpolysaccharides such as dextran; and combinations of two or morethereof.

The mechanism by which these water-soluble polymers are gelled withpolyvalent metallic cations is not completely clarified, but an egg boxmodel is proposed wherein two carboxyl groups in the polymer arecrosslinked via a coordinate bond with one divalent cation to gel thewater-soluble polymer. Accordingly, when divalent cations are present ina sufficient amount relative to carboxyl groups in the polymer, a gel ofhigh density of crosslinkage is obtained, while when the amount ofdivalent cations is limited at a low level, a gel of low density ofcrosslinkage is obtained. In view of the above, it is preferable thatafter the amount of carboxyl groups in the “water-soluble polymergelling by polyvalent metallic cations” is grasped, the contents of the“insoluble salt releasing polyvalent metallic cations under acidicconditions” and the “water-soluble polymer gelling by polyvalentmetallic cations” are determined, whereby the properties of gel formedin the stomach can be controlled and the sustained release of medicinescan be regulated. In consideration of the egg box model, the“water-soluble polymer gelling by polyvalent metallic cations”preferably has carboxyl group or sulfonic acid group, or both of thesegroups in the structure thereof.

Preferable among those described above are alginic acid, alginate,pectin, a combination of alginic acid or alginate and pectin, gellangum, a combination of pectin and gellan gum, a combination ofcarrageenan and locust bean gum, and a combination of gellan gum andarabic gum, most preferably sodium alginate and gellan gum. When a gelof high physical strength is required, pectin is LM pectin with a lowdegree of methylation, and when so high physical strength is notdesired, HM pectin may also be used.

The physical strength of the gel can be regulated not only by selectingthe water-soluble polymer or by adding polyvalent metallic cations butalso by a combination of two or more water-soluble polymers. Forexample, alginic acid or alginate and pectin, gellan gum and pectin, orcarrageenan and locust bean gum are combined and their compounding ratiois devised, whereby a gel of high physical strength can be formed inliving body. The liquid matrix transformed into a gel of high physicalstrength in living body is not immediately disintegrated in the stomach,is transferred to the small intestine by peristalsis of the stomach, andthen gradually disintegrated in the small intestine and thereafter toexhibit excellent sustained release of the medicine.

Further, the liquid matrix itself and the gel can be modified by addingwater-soluble polymers, for example polyethylene glycol, polyethyleneglycol/polypropylene glycol block copolymer and the like; animalproteins such as gelatin, casein, and collagen; or starch such assoluble starch, and methyl starch.

When the liquid matrix of the present invention is applied to an anti-H.pylori preparation, the active medicine remains for a longer time in thestomach than in merely drinking the medicine with water, and thus theoriginal activity of the medicine can be exhibited more effectively thanby conventional administration of 3 medicines. Further, when the liquidmatrix of the present invention gels in the stomach, it could becrosslinked with a mucous layer of the stomach to exhibit efficacy for along time. That is, H. pylori itself is weak to strong acidity, and isthus protected by the surface mucous membrane of the stomach, andbecause the mucous layer is coherent to the gel, the medicine containedin the anti-H. pylori oral liquid preparation of the invention canexhibit efficacy without undergoing the influence of stomach acid.

As described above, the water-soluble polymer are selected and combined,metallic anions are added or not added, and the amount thereof isregulated, whereby a gel having various properties by which the gel isgradually disintegrated in the stomach or is stable in the stomach anddisintegrated in the small intestine can be formed in the living body toachieve sustained release for exhibiting the activity of the medicine tothe maximum degree.

The physical strength of the gel formed from the liquid matrix of thepresent invention should have a breaking stress of about 3.00×102 N/m².This is because when the breaking stress is less than this strength, thesustained release of the medicine cannot be maintained. The “about3.00×10² N/m² or more” refers to a numerical value which upon beingrounded off, becomes at least 3.00×10² N/m², and refers specifically toa numerical value of 2.95×10² N/m² or more. The breaking stress ispreferably 8.70×10² N/m² or more, most preferably 2.00×10³ N/m² or more.

The relationship of the concentration of the water-soluble polymercontained in the matrix of the present invention with the viscosity ofthe liquid matrix or the physical strength of the gel is significantlyvaried depending on the properties of the water-soluble polymer, andthus the concentration is not particularly limited. However, it isrecommended that the concentration be generally 0.01 to 10% by mass.

The “insoluble salt releasing polyvalent metallic cations under acidicconditions” used in the present invention is insoluble or sparinglysoluble in an aqueous neutral or weakly basic solution, but is dissolvedunder acidic conditions to release polyvalent metallic cations. Theinsoluble salt is not particularly limited insofar it ispharmacologically acceptable, but a salt containing a divalent ortrivalent metallic cation is preferable. Such insoluble salt includesalkaline earth metal salts of inorganic acid such as barium carbonate,barium sulfate, strontium carbonate, calcium carbonate, calciumphosphate, magnesium dihydrogen phosphate, magnesium aluminate silicate,magnesium aluminate metasilicate, calcium hydrogen phosphate anhydride,and calcium hydrogen phosphate; light metal salts of inorganic acid suchas synthetic aluminum silicate and aluminum phosphate; hydroxides suchas magnesium hydroxide, magnesium alumina hydroxide, aluminum hydroxide,and dry aluminum hydroxide gel; alkali earth metal oxides such asmagnesium oxide; synthetic hydrotalcite; dihydroxyaluminum aminoacetateand dihydroxyaluminum aminoacetate; and sucrose ester aluminum salts.

The term “insoluble” means that generally at least 10,000 g water isrequired to dissolve 1 g sample, and “sparingly soluble” means that1,000 to 10,000 g water is required to dissolve 1 g sample. Thesolubility of the insoluble salts can be higher than the above rangeinsofar as the object of the present invention can be achieved.

The content of the “insoluble salt” is preferably about 10% by mass orless, more preferably about 5% by mass or less, relative to the totalweight of the liquid matrix or the preparation. A number after the term“about” refers to a number which is previously rounded off; for example,“about 10% by mass or less” specifically refers to “less than 10.5% bymass”. The lower limit of the “insoluble salt” contained is determinedby the amount of the “water-soluble polymer gelling by metallic cations”contained and by a desired degree of crosslinkage of gel in the stomach.

The molar ratio of the multivalent metallic cation possessed by theinsoluble salt to the carboxyl group or sulfonic acid group in thestructure of the water-soluble polymer is preferably 1 to 10, morepreferably 3 to 5.

The liquid matrix according to the present invention is prepared bydissolving the “water-soluble polymer gelling under acidic conditions”in water.

The “water” used herein is not particularly limited insofar as it is apharmacologically acceptable aqueous solvent, the water is preferablydistilled water or physiological saline, particularly preferablydistilled water.

When the “insoluble salts releasing polyvalent metallic cations underacidic conditions” is to be contained in the liquid matrix according tothe present invention, it is preferable that the water-soluble polymeris first dissolved in water, and then the insoluble salt is addedthereto. This is because the insoluble salt is insoluble or sparinglysoluble in water. To disperse the insoluble salt uniformly in the liquidmatrix, sonication or the like may be conducted. The prepared liquidmatrix is preferably subjected to sterilization treatment such ashigh-pressure sterilization for pharmacological use.

When the insoluble salt is to be contained, the pH of the liquid matrixaccording to the present invention should be neutral or basic so as notto dissolve the insoluble salt, or should be neutral or weakly basic inconsideration of the stability of medicine added. Further, when themedicine added contains polyvalent metallic cations or shows acidity,the pH of the liquid matrix should be regulated in advance inconsideration of the properties of the medicine. The acid or base usedin this regulation is not particularly limited insofar as it ispharmacologically acceptable, but a solution of hydrochloric acid orsodium hydroxide is preferably used.

The liquid matrix according to the present invention may be blendeddepending on the intended object with salts, surfactants, coloringmatters, flavoring ingredient, acidic tasting materials, sweeteners,preservatives (parabene, sodium benzoate and the like), as long as theyare pharmaceutically acceptable. The scope of the present invention isnot limited thereto.

The viscosity of the prepared liquid matrix is preferably 3.0×10⁻¹ Pa.sor less, more preferably about 2.0×10⁻¹ Pa.s or less, still morepreferably about 1.0×10⁻¹ Pa.s or less, further more preferably 1.0×10⁻¹Pa.s or less. This is because when the viscosity is higher than theabove range, infants or patients with difficulty in swallowing sufferfrom swallowing of the liquid matrix of the present invention.Accordingly, it is recommended that the viscosity of the liquid matrixbe lower for patients having more difficulty in swallowing. The “about2.0×10⁻¹ Pa.s or less” refers to a number which upon being rounded off,becomes 2.0×10⁻¹ Pa.s or less, and refers specifically to a number lessthan 2.5×10⁻¹Pa.s. Similarly, “about 1.0×10⁻¹ Pa.s or less” refers to anumber of less than 1.5×10⁻¹ Pa.s.

The “medicine” incorporated together with the liquid matrix into theoral liquid preparation of the present invention is not particularlylimited, and not only one medicine but also two or more medicines may beincorporated. A soluble and stable medicine may be mixed as it is, and asparingly soluble medicine may be formed into a conjugate withcyclodextrin in order to solubilize and stabilize the medicine.Alternatively, a sparingly soluble medicine may be dispersed orsuspended as it is. Because the liquid matrix of the present inventionhas a dispersing effect on the medicine so that even if the medicine isinsoluble or sparingly soluble, the medicine can be dispersed thereinand prevented from being precipitated.

The “medicine” incorporated into the oral liquid preparation of thepresent invention includes agents for the nervous system such ashypnotic analgesics, antianxiety agents, anti-epilepsy agents,antipyretic sedative antiphlogistics, anti-Parkinson agents, agents forpsychosis and neurological disorders, and agents for the cold; agentsfor circulation organs such as agents for arrhythm, diuretics, bloodpressure depressants, vasoconstrictors, vasodilators, and agents forhyperlipemia; agents for respiratory organs such as respiratorystimulant, cough suppressant, expectorants, anti-cough expectorants, andbronchodilator; agents for digestive organs such as antidiarrhoic,antiflatulent, medicines for digestive ulcer, medicines for stomachdigestion, laxative, medicines for gallbladder, and medicines forstomach ulcer and duodenal ulcer; various hormones; medicines forurinogenital organs and anus such as medicines for urinary organs,medicines for generative organs, and uterus shrinking medicines;metabolic pharmaceutical preparations such as vitamins, revitalizer,medicines for blood and body fluid, medicines for hepatic diseases,antidotes, medicines for habitual poisoning, gouty medicines, enzymespreparations, diabetic medicines, cell activators, antitumor agents,medicines for allergies, antibiotics including anti-pylori agents,medicines for chemotherapy, biological preparations, parasiticides,opium alkaloid drugs, and non-alkaloid drugs. The medicines used in theinvention are not limited in the above.

When dl-methylephedrine hydrochloride, noscapine, dextromethorphanhydrobromide, dihydrocodeine phosphate or a dihydrocodeine/ephedrineblend used in therapy of infant asthma is incorporated as the medicineinto the liquid matrix of the present invention, the activity of themedicine can be maintained and the frequency of administration can bereduced, and thus it is very effective for treatment of infants.

In the therapy of patients with terminal cancer, morphine preparationsor codeine preparations are used singly or in combination for thepurpose of relieving cancerous pain, and these are solid pharmaceuticalpreparations. Easily swallowed preparations are desired for patientswith terminal cancer, but when these preparations are used as liquid,the preparations cannot be durable. When the liquid matrix of thepresent invention is used, the preparations can be administered asdurable pain reducers into the patients.

Further, when the preparation of the invention is used for stomach ulceror gastritis, anti-inflammatory ulcer agents can be added. Such agentsinclude methyl thionine preparations, azulene preparations, herbextracts, aceglutamide, aldioxa, urogastron, ecabet sodium, cetraxatehydrochloride, pirenzepine hydrochloride, benexate hydrochloride,enprostyl, ornoprostil, gefarnate, scralfate, sulpiride, sofalcon,teprenone, troxipide, plaunotol, proglumide, polaprezinc, irsogladinemaleate and misoprostol.

Regardless of the foregoing, the oral liquid preparation blended withthe medicine having an anti-H. pylori activity exhibits a particularlyhigh effect. That is, the oral liquid preparation of the presentinvention is “liquid”, and can thus be easily administered to theelderly or persons having difficulty in swallowing. After ingestion intothe stomach, it spreads to every hole and corner of stomach wall havinga complicated villous structure, and enters into crypts to which a gelpreparation or the like hardly enters, followed by gelling with thestrong acidity of hydrochloric acid as a major component of stomach acidsecreted from the fundic gland. Accordingly, the liquid preparation ofthe present invention can protect the stomach mucous membrane throughoutthe stomach and can sustainably release the efficacy component to anaffected area, and is thus very effective in treatment of gastritis andstomach ulcer. Further, when the liquid matrix of the present inventiongels in the stomach, it could be crosslinked with a mucous layer of thestomach to exhibit efficacy for a long time. That is, H. pylori itselfis weak to strong acid and is protected by the surface mucous membraneof the stomach, and because the gel is coherent to this mucous layer,the medicine contained in the anti-H. pylori oral liquid preparation ofthe present invention can exhibit the efficacy without undergoing theinfluence of stomach acid.

The “medicine exhibiting an anti-H. pylori activity” is not particularlylimited insofar as it is effective against H. pylori andpharmacologically acceptable. The examples thereof include penicillinantibiotics such as amoxicillin, macrolide antibiotics such asclarithromycin, roxithromycin, and azithromycin, tetracyclineantibiotics such as minocycline hydrochloride, cepham antibiotics suchas cephachlor, cephalexin, and cefdinir, and pyridonecarboxylic acidsynthetic antibacterial agents such as ofloxancin, tosufloxacintosylate, levofloxancin, norfloxacin, and gatifloxacin, andmetronidazole, from which at least one member can be selected and used.

Particularly preferable among these are amoxicillin, clarithromycin,roxithromycin, minocycline hydrochloride, cephachlor, cephalexin,ofloxancin, tosufloxacin tosylate, and levofloxancin, and it isrecommended that two or more thereof are simultaneously administered.The medicines are not particularly limited insofar as theirantibacterial action on H. pylori is strong.

Regardless of the foregoing, the oral liquid preparation blended withthe “medicine” having a therapeutic effect on stomach ulcer or duodenalulcer exhibits a particularly high effect. This is because unlike theconventional anti-ulcer agent, the medicine can be released graduallyand directly to an affected area, and thus the utilization of themedicine is high, and side effects can be reduced.

The “medicine having a therapeutic effect on stomach ulcer or duodenalulcer” can be classified into medicines having effect of “inhibitingattack factor” mainly inhibiting secretion of stomach acid andinhibiting an attack factor causing ulcer and “promoting protectionfactor” mainly having a protective effect on stomach mucous membrane andan effect of promoting repair of ulcerous sites. The medicine used inthe present invention is not particularly limited insofar as it isacceptable under the Pharmaceutical Affairs Law. However, acidregulators such as aluminum hydroxide and sodium hydrogen carbonatedirectly neutralizing stomach acid are preferably not used. This isbecause the liquid matrix according to the present invention may beprevented from gelling, to fail to exhibit the sustained release of themedicine.

The medicine having effect of “inhibiting attack factor” and therapeuticeffect on stomach ulcer or duodenal ulcer includes, for example, protonpump inhibitors such as omeprazole, lansoprazole, and rabeprazole; H2blockers such as cimetidine, ranitidne, and famotidine; selectivemuscaline receptor antagonists such as pirenzepine; and anti-gastrinagents such as proglumide, secretin, and urogastrone. The medicinehaving effect of “promoting protection factor” and therapeutic effect onstomach ulcer or duodenal ulcer includes, for example, ulcerous lesionprotecting agents such as sucralfate, and azulene; tissue repairpromoters such as aldioxa, gefarnate, ecabet sodium, and L-glutamine;mucous fluid production/secretion promoters such as teprenone,plaunotol, ornoprostil, enprostil, and rebamipide; stomach mucousmembrane finite circulation improvers such as cetraxate hydrochloride,sofalcon, sulpiride, and benexate betadex hydrochloride; localanti-inflammatory agents such as azulene sulfonate sodium; andprostaglandin such as PGE1 (alprostadil alphadex) and PGE2.

Among the medicine having effect of “inhibiting attack factor” and“promoting protection factor”, the medicine having effect of “promotingprotection factor” is more preferable. This is because when stomach acidsecretion itself is inhibited, the protecting ability of stomach acid isreduced, and thus infection of bacteria may occur.

The “medicine having herapeutic effect on stomach ulcer or duodenalulcer” is preferably prostaglandin or a derivative thereof. This isbecause the prostaglandin has results as a medicine for digestive tractulcer, and the effect of the liquid preparation of the inventioncontaining the prostaglandin is proven by the Examples described later.

The time of blending the medicine with the liquid matrix of the presentinvention is not particularly limited. The medicine may be mixed justbefore administration. For example, medicines, of which stability isdeteriorated upon dissolution in water, are mixed preferably just beforeadministration.

Even if the medicine is incorporated into the liquid matrix of thepresent invention, the viscosity thereof before and after incorporationis hardly changed. The viscosity after incorporation, just as theviscosity of the liquid matrix, is preferably 3.0×10⁻¹ Pa.s or less,more preferably about 2.0×10⁻¹ Pa.s or less, still more preferably about1.0×10⁻¹ Pa.s or less, further more preferably 1.0×10⁻¹ Pa.s or less.Sterilization treatment such as high-pressure sterilization may beconducted after the medicine was blended.

The present invention was constituted as described above, and the liquidmatrix of the present invention has an effect of masking bitter tastesof medicine and the like, and is thus useful as a swallowing assistantfor the medicine, and exhibits the sustained release of the medicine bygelling in the living body.

Accordingly, the liquid oral preparation having the liquid matrix of thepresent invention as the component has the above-described effect, iseasily swallowed and exhibits sustained release of the medicine, andthus even if it contains medicine having high side effects as component,the efficacy can be sustained without rapidly increasing its bloodconcentration, and the frequency of administration can be reduced.

As the oral liquid preparation of the present invention, the onecontaining an anti-H pylori agent is highly effective. This is becausein eradication therapy of H. pylori, for which no effective therapeuticmethod has been established, the amount of the antibiotic blended can bereduced without using a proton pump inhibitor, and the side effect canthereby be inhibited. Further, the liquid preparation containingmedicine having therapeutic effect on stomach ulcer or duodenal ulcercan directly act on ulcerous legions, thus exhibiting a very hightherapeutic effect thereon.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the relationship between the strength (breaking stress) ofgel and release of riboflavin from the gel.

FIG. 2 shows sustained release of riboflavin from the oral liquidpreparation of the present invention.

FIG. 3 shows sustained release of acetaminophen from the oral liquidpreparation of the present invention.

FIG. 4 shows autoclaved states of the liquid matrix of the presentinvention and a comparative example.

FIG. 5 shows sustained release of riboflavin from the oral liquidpreparation of the present invention containing two kinds ofwater-soluble polymers.

FIG. 6 shows sustained release of riboflavin from the oral liquidpreparation of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention is described in more detail byreference to the Examples and Preparation Examples, but the scope of thepresent invention is not limited thereto.

EXAMPLE 1

Sodium alginate was added to distilled water to prepare 10 ml aqueoussolutions of a water-soluble polymer at various concentrations, andvarious amounts of calcium carbonate or calcium phosphate were added asthe insoluble salt to prepare liquid matrixes. 5 ml of in the JapanesePharmacopoeia Disintegration Test Liquid 1 was added to each liquidmatrix, and a reproduction test was conducted where the liquid matrix ofthe present invention was assumed to be introduced into the stomach, andthe state of gelling was observed. The results are shown in Tables 1 and2. TABLE 1 Alginic acid [number of moles Calcium carbonate of carboxylgroup 1 mg 10 mg 20 mg 40 mg 60 mg 80 mg 100 mg is shown in ( )] (0.01mmol) (0.1 mmol) (0.2 mmol) (0.4 mmol) 0.6 mmol) (0.8 mmol) (1 mmol)0.01% by mass x x — — — — x (0.005 mmol) 0.1% by mass x x x x x x x(0.05 mmol) 0.2% by mass — x Δ Δ Δ Δ Δ (0.09 mmol) 0.4% by mass Δ Δ Δ Δ∘ ∘ ∘ (0.2 mmol) 0.6% by mass Δ Δ ∘ ∘ ∘ ∘ ∘ (0.3 mmol) 0.8% by mass Δ Δ∘ ∘ ∘ ∘ ∘ (0.4 mmol) 1% by mass Δ Δ ∘ ∘ ∘ ∘ ∘ (0.5 mmol)∘: Uniform gelling.Δ: Heterogeneous gelling.x: No gelling.

TABLE 2 Alginic acid [number of moles Calcium phosphate of carboxylgroup 1 mg 10 mg 20 mg 40 mg 60 mg 80 mg 100 mg is shown in ( )] (0.0032mmol) (0.032 mmol) (0.064 mmol) (0.13 mmol) (0.19 mmol) (0.26 mmol)(0.32 mmol) 0.01% by mass x x — — — — x (0.005 mmol) 0.1% by mass x x xx x x x (0.05 mmol) 0.2% by mass — x Δ Δ Δ Δ Δ (0.09 mmol) 0.4% by massΔ Δ Δ Δ ∘ ∘ ∘ (0.2 mmol) 0.6% by mass Δ Δ ∘ ∘ ∘ ∘ ∘ (0.3 mmol) 0.8% bymass Δ Δ ∘ ∘ ∘ ∘ ∘ (0.4 mmol) 1% by mass Δ Δ ∘ ∘ ∘ ∘ ∘ (0.5 mmol)∘: Uniform gelling.Δ: Heterogeneous gelling.x: No gelling.

Components constituting in sodium alginate are sodium β-D-mannuronateand sodium α-L-gluronate, and both the molecular weights of the sodiumsalts of these such sugar acids are about 217 and one carboxyl group ispossessed by one sugar. Therefore, the number of moles of carboxylgroups in sodium alginate at each concentration can be roughlycalculated.

From the results in Tables 1 and 2, it was found that when the insolublesalt releasing metallic cations is contained to uniformly gel the liquidmatrix of the present invention, the molar ratio of the metallic cationpossessed by the insoluble salt to the carboxyl group or sulfonic acidgroup in the structure of water-soluble polymer is preferably 1 or more.

EXAMPLE 2

Two kinds of water-soluble polymers were mixed to prepare liquidpreparations to transform them into gels having varying gel strength(gel shear stress), and a test of sustained release of medicine wasconducted.

κ-Carrageenan and locust bean gum were added in a varying mixing ratioas the water-soluble polymers to 100 ml distilled water and stirredsufficiently to prepare a plurality of liquid matrixes to be transformedinto gels having varying gel strength. Further, riboflavin was added ata final concentration of 0.02% and adjusted to pH 7.4 to prepare liquidpreparations.

1 ml of this riboflavin-liquid matrix was dropped along a tube wall intoa tube containing 30 ml Japanese Pharmacopoeia Disintegration TestLiquid 1, and a reproduction test was conducted where theriboflavin-liquid matrix was assumed to be introduced into the stomach.The riboflavin-liquid matrix gelled upon contacting with theDisintegration Test Liquid 1. The strength of each gel was determined interms of breaking stress (N/m²) by Yamaden Creep Meter HC2-3805.

The gel was completely introduced into the Disintegration Test Liquid 1and then stirred at 37° C. for 120 minutes, and the release ofriboflavin was measured. The riboflavin thus released wascalorimetrically quantified by measuring absorbance at 445 nm accordingto C-2660 to 2667 in Manual of the Japanese Pharmacopoeia 13th ed.(1996) published by Hirokawa Shoten. Assuming that the amount ofriboflavin in the original gel was 100, the amount (%) of riboflavinreleased to the Disintegration Test Liquid 1 was calculated. Therelationship between the gel strength and the degree of release ofriboflavin is shown in FIG. 1.

As shown in FIG. 1, riboflavin is strongly maintained in the gel whenthe strength of the gel is high, and the medical is sustainedlyreleased. That is, the gel can be evaluated as having sustainedreleasability when the medicine remains in the gel even after stirringat 37° C. for 120 minutes. On the other hand, when the gel strength islow, riboflavin is immediately released, and the gel cannot showsustained release. That is, usually, when gel not showing sustainedrelease is dipped in the Disintegration Test Liquid 1 at 37° C., the gelimmediately releases medicine, and the shape of the gel is lost in about20 minutes. In this experiment, the gel was regarded as having theminimum strength for attaining sustained release when 10% or more of themedicine remained in the gel after dipping in the Disintegration TestLiquid 1 at 37° C. for 120 minutes. From the result, the rupture stresswas about 3. 00×102 N/m².

EXAMPLE 3

1 g of sodium alginate or 1 g of LM pectin was added to and completelydissolved in 100 ml distilled water, and then 1 g of calcium carbonatewas added. The mixture was adequately stirred to make two liquid matrix.To this solution, 100 mg of riboflavin was added and dissolved to adjustthe pH to 7.4.

1 ml of this riboflavin-liquid matrix was gelled by treating it in thesame manner as in Example 2. When the strength of each gel was measuredin the same manner as in Example 2, the strengths of the gels formedfrom 1% sodium alginate and 1% LM pectin were 1.02×10⁴ N/m² and 5.59×10³N/m², respectively. The amount of riboflavin released from the gel wasmeasured. Assuming that the amount of riboflavin in the original gel was100, the amount (%) of riboflavin released to the Disintegration TestLiquid 1 was calculated. The results are shown in FIG. 2.

As shown in FIG. 2, it was found that in both the case where alginicacid and LM-pectin was used as the water-soluble polymer, riboflavin wassustainedly released without rapidly being released to the testsolution. Accordingly, it was proved that the oral liquid preparation ofthe present invention exhibits excellent sustained releasability.

EXAMPLE 4

1 g of sodium alginate was added to 100 ml of distilled water anddissolved completely, and 1 g calcium carbonate was added thereto. Themixture was stirred sufficiently to prepare a liquid matrix. 10 mg ofacetaminophen (Yoshitomi Fine Kagaku Co., Ltd.) was added thereto toadjust pH to 7.4.

1 ml of this acetaminophen-liquid matrix was dropped into 100 ml of theJapanese Pharmacopoeia Disintegration Test Liquid 1, and a reproductiontest was conducted where the acetaminophen-liquid matrix was assumed tobe introduced into the stomach. The dropped acetaminophen-liquid matrixwas immediately gelled. The strength of the gel was 1.02×10⁴ N/m².Release of the acetaminophen from this gel was measured. The releasedacetaminophen was calorimetrically quantified by measuring absorbance at244 nm according to C-69 to C-73 in Manual of the JapanesePharmacopoeia, 13th ed., Hirokawa Shoten (1996). Assuming that theamount of acetaminophen in the original gel was 100, the amount (%) ofacetaminophen released into Disintegration Test Liquid 1 was calculated.The results are shown in FIG. 3.

As shown in FIG. 3, it was revealed that when the acetaminophen-liquidmatrix was introduced into the stomach, the water-soluble polymer wasgelled, and acetaminophen was sustainedly released. Accordingly, it wasevidenced that the oral liquid preparation of the present inventionshows excellent sustained releasability.

EXAMPLE 5

The acetaminophen-liquid matrix prepared in Example 4 was sterilized andtreated at high pressure at 121° C. for 30 minutes, followed by beingleft to reduce the pressure, whereby a test sample was obtained.

As a comparative example, an acid-regulating composition having stableviscosity was prepared by referring to a description of JapaneseUnexamined Patent Publication No. Hei 8-99885. That is, 2.5 g of sodiumalginate and 28 g of aluminum hydroxide/magnesium carbonate gel (56%Al₂O₃, 4% MgO) were added to about 75 ml of pure water and stirred atabout 80° C. for 30 minutes. This heated reaction mixture was rapidlymixed under stirring with 400 ml aqueous suspension of 35 g magnesiumcarbonate kept at about 25° C. 47.5 g of sodium alginate was added tothis mixture, and 1 g of xanthane gum, 15 g of calcium carbonate and 10g of potassium hydrogen carbonate were added respectively thereto, andthe mixture was adjusted to 1 L with pure water. The comparative productthus produced was sterilized at high pressure in the same manner as forthe acetaminophen-liquid matrix of the present invention.

The states of both the samples after high-pressure sterilization areshown in FIG. 4.

As shown in FIG. 4, the oral liquid preparation of the present inventionwas maintained stably even after high-pressure sterilization, while thecomparative product was separated completely into an aqueous layer and agel layer. It was thus found that the operativeness for sterilization ofthe oral liquid preparation of the present invention is extremely high.

EXAMPLE 6

In the same manner as in Example 2, two kinds of water-soluble polymerswere added to and completely dissolved in 100 ml distilled water to form(i) 0.5% alginic acid-0.5% pectin and (ii) 1% alginic acid-l% pectinrespectively, and then 1 g of calcium phosphate was added thereto. Themixture was sufficiently stirred to prepare liquid matrixes. 100 mg ofriboflavin was added to and dissolved in each solution, to adjust the pHto 7.4.

The two prepared liquid preparations were gelled by dipping for 6 hoursin Japanese Pharmacopoeia Disintegration Test Liquid 1. The strength ofthe gel was 3.02×10³ N/m² for 0.5% alginic acid-0.5% pectin and 1.00×10⁴N/m² for 1% alginic acid-1% pectin. The gel was removed, and theadhering Japanese Pharmacopoeia Disintegration Test Liquid 1 was removedby a filter paper. Then, the gel was dipped in Japanese PharmacopoeiaDisintegration Test Liquid 2, whereby a reproduction test was conductedwherein the riboflavin-liquid matrix was assumed to be transferred viathe stomach into the small intestine. The release of riboflavin from thegel was measured in the same manner as in Example 2. The results areshown in FIG. 5.

As shown in FIG. 5, it was found that by selecting the water-solublepolymer as the constituent component or by combination thereof of theoral liquid preparation of the present invention, the physical strengthand the disintegration of the gel can be regulated not only in thestomach but also in the small intestine, to demonstrate excellentsustained release.

EXAMPLE 7

Aqueous sodium alginate solutions prepared at various concentration(viscosity) were used in healthy 6 male adults as examinees, and anorganoleptic test was conducted to examine easiness of administration.The results are shown in Table 3. TABLE 3 Concentration of sodiumalginate (wt %) 1.0 1.2 1.4 1.6 1.8 2.0 Viscosity (Pa · S) 4.0 × 10⁻²6.0 × 10⁻² 8.0 × 10⁻² 1.0 × 10⁻¹ 2.0 × 10⁻¹ 5.0 × 10⁻¹ Number of persons6 6 6 6 5 0 who can administer it Number of persons 0 0 0 0 1 4 who canadminister it with slight difficulty Number of persons 0 0 0 0 0 2 whohardly administer it

From the results in this example, it was revealed that in considerationof easiness of administration, the viscosity of the liquid matrix ispreferably 3.0×10⁻¹ Pa.s or less.

EXAMPLE 8

20 ml of 1% aqueous sodium alginate solution into 50 mg of magnesiumchloride had been added as bitter-taste component was used in healthy 6male adults as examinees, and an organoleptic test was conducted toexamine the masking effect on the bitter taste. As a comparativeexample, 20 ml of water containing 50 mg of magnesium chloride was used.The results are shown in Table 4. TABLE 4 Evaluation of masking effecton bitter taste ⊚ ◯ X 4 persons 2 persons 0 person⊚: Significant relaxation of bitter taste◯: Slight relaxation of bitter tasteX: No relaxation of bitter taste

From the results of this test, it was revealed that the liquid matrix ofthe present invention has a masking effect on the bitter taste of themedicine.

EXAMPLE 9

Gellan gum and LM pectin were dissolved in distilled water to prepare aliquid matrix containing each component at a concentration of 0.5%. 10mg of riboflavin was added to and dissolved in 10 ml of this liquidmatrix, to adjust the pH to 7.4.

1 ml of the riboflavin-liquid matrix was dropped into JapanesePharmacopoeia disintegration Disintegration Test Liquid 1, and areproduction experiment was conducted wherein the riboflavin-liquidmatrix was assumed to be transferred into the stomach. As a result, thedropped riboflavin-liquid matrix was gelled upon dropping. The strengthof the gel was 3.00×10⁴ N/m². The release of riboflavin released fromthe gel was measured in the same manner as in Example 2. The release ofthe medicine into the Japanese Pharmacopoeia Disintegration Test Liquid2 was also measured in the same manner as in Example 6. The results areshown in FIG. 6.

As shown in this result, the riboflavin in the gel was eluted graduallyinto the Disintegration Test Liquid 1 and 2 without being rapidlyreleased. From this result, it was evidenced that the oral liquidpreparation of the present invention shows excellent sustained releaseboth in the stomach and in the small intestine.

EXAMPLE 10

The liquid preparations of the invention having compositions in Tables 5to 9 were prepared. TABLE 5 1 2 3 4 5 6 7 Amoxicillin 0.75 g 0.5 g 0.5 g0.5 g 0.5 g Clarithromycin 0.2 g 0.2 g 0.2 g 0.3 g Roxithromycin 0.15 g0.15 g Pectin 4 g 0.2 g 0.02 g 0.01 g Gellan gum 1 g 0.05 g 0.03 g 0.04g 0.03 g Sodium alginate 0.05 g 0.05 g Calcium carbonate 0.05 g 0.05 gWhite soft sugar 20 g 1 g 1 g 1 g 1 g 1 g 1 g Distilled water balancebalance balance balance balance balance balance Total amount 200 g 10 g10 g 10 g 10 g 10 g 10 g

TABLE 6 8 9 10 11 12 13 Cefaclor 0.25 g 0.25 g 0.25 g Cefalexin 0.5 g0.5 g 0.5 g Amoxicillin 0.5 g 0.5 g Clarithromycin 0.2 g Pectin 0.04 g0.02 g 0.02 g Gellan gum 0.05 g 0.05 g Sodium alginate 0.04 g 0.05 g0.05 g Calcium carbonate 0.03 g 0.04 g 0.05 g 0.05 g D-Sorbitol 1 g 1 g1 g 1 g 1 g 1 g Distilled water balance balance balance balance balancebalance Total amount 10 g 10 g 10 g 10 g 10 g 10 g

TABLE 7 14 15 16 17 18 Ofloxacin 0.2 g 0.2 g Sparfloxacin 0.1 gTosufloxacin tosilate 0.15 g 0.15 g Amoxicillin 0.5 g 0.5 g 0.5 gClarithromycin 0.2 g 0.2 g Pectin 0.02 g 0.02 g Gellan gum 0.05 g 0.05 gCarrageenan 0.05 g 0.05 g 0.05 g Calcium carbonate 0.04 g 0.05 g 0.05 gD-Sorbitol 1 g 1 g 1 g 1 g 1 g Distilled water balance balance balancebalance balance Total amount 10 g 10 g 10 g 10 g 10 g

TABLE 8 19 20 21 22 23 24 Minocycline HCl 0.1 g 0.1 g 0.1 g Nalidixicacid 1 g Norfloxacin 0.2 g 0.2 g Clarithromycin Amoxicillin 0.5 g 0.5 g0.5 g Pectin 0.01 g 0.03 g 0.02 g 0.01 g 0.01 g Gellan gum 0.05 g 0.07 g0.04 g 0.04 g Sodium alginate 0.03 g 0.05 g Calcium carbonate 0.05 gWhite soft sugar 1 g 1 g 1 g 1 g 1 g 1 g Distilled water balance balancebalance balance balance balance Total amount 10 g 10 g 10 g 10 g 10 g 10g

TABLE 9 25 26 27 28 29 Levofloxacin 0.1 g 0.1 g Metronidazole 0.25 g0.25 g Bismuth subcarbonate 1 g Clarithromycin 0.2 g Amoxicillin 0.5 g0.5 g 0.5 g 0.5 g Pectin 0.02 g 0.02 g 0.02 g Gellan gum 0.05 g 0.05 g0.05 g Sodium alginate 0.05 g 0.05 g Calcium carbonate 0.05 g 0.05 gD-Sorbitol 1 g 1 g 1 g 1 g 1 g Distilled water balance balance balancebalance balance Total amount 10 g 10 g 10 g 10 g 10 g

When each of 1 ml liquid preparations shown in Nos. 2, 3, 6, 8, 9, 10,14, 16, 21 and 26 in the tables was added gently to a Petri dishcontaining 10 mL artificial stomach fluid (the Japanese PharmacopoeiaDisintegration Test Liquid 1), all of liquid preparation gelledimmediately upon contacting with the artificial stomach fluid.

The gelled preparation was dipped in 10 ml culture of H.pylori (CFU:1×10⁷, 1×10⁸, 1×10⁹/ml, Brucella broth containing 10% inactivated horseserum) and cultured under slight aerobic conditions at 37° C. for 24hours by using Campy Pak (BBL). Similarly, only the gel not containingthe antibacterial agent was used as a negative control, and 0.5 g ofamoxicillin and 0.2 g of clarithromycin were used as positive controls,and these were added and cultured.

After 24 hours, each culture was sprayed onto M-BHM pylori agar mediumcontaining 10% inactivated horse serum (K. K. Nikken Seibutsu IgakuKenkyusho) and cultured at 37° C. for 7 days, and then whether H. pyloriproliferated or not was examined for evaluation. The determination ofthe antibacterial activity was evaluated as positive when the bacteriawere eliminated or evidently reduced, and as negative (−) when thebacteria proliferated. The results are shown in Table 10 below. TABLE 10Gel H. pylori (CFU; Anti- colony forming unit/mL) bacte- 1 × 10⁷ 1 × 10⁸1 × 10⁹ Control Negative rial − − − Positive agent* + + + Gel No.2 + + + preparation* 3 + + + 6 + + + 8 + + + 9 + + + 10 + + + 14 + + +16 + + + 21 + + + 26 + + +

From the above result, it was revealed that the liquid preparation ofthe present invention gelled rapidly with stomach fluid, and indicatedthe same activity as by administration of the antibacterial agent as itwas.

The antibiotic is generally unstable to strong acid, and upon oraladministration, its activity is reduced with stomach acid. On the otherhand, in the liquid preparation of the present invention, theantibacterial agent is protected with the gel, and could thus maintainthe antibacterial activity even in the stomach in order to treat H.pylori infection.

EXAMPLE 11

First, according to a known method (Hirayama et al., Journal ofGastroenterogy, Vol. 31, pp. 755-757 (1996)), H. pylori (ATCC43504) wascultured under slight aerobic conditions in Brucella broth (BBL)containing 10% inactivated horse serum to prepare a culture of 1×10⁹ CFU(colony forming unit)/ml.

Then, male mongolian gerbil (Meriones unguiculatus; MGS/Sea, weightabout 60 g), 3 to 4 animals/group, were fasted for 24 hours, and then200 μl of the Helicobacter pylori culture solution (2×108 CFU) wasinoculated via an oral probe for rat into the stomach.

Seven days after inoculation, an antibacterial agent was administeredtwice (morning and evening) every day for 2 days according to a knownmethod (Shimidzu et al., Cancer Research, Vol. 60, pp. 1512-1514(2000)).

As the antibacterial agent, liquid preparation No. 23 in Example 10(minocycline hydrochloride added as the antibacterial agent to theliquid matrix consisting of pectin and gellan gum) was administered. Thedose in terms of the amount of the antibacterial agent administered was17 mg/body weight in each administration.

As the control, 0.5% CMC solution only and a combined medicine of 3agents, that is, insurance-applicable lansoprazole (proton pumpinhibitor), amoxicillin (antibiotic) and clarithromycin (antibiotic) ina dose of 10, 3, 30 mg/body kg, respectively, were administered.

In judgment of microbial eradication, collected stomach mucous membranetissues were cultured under slightly aerobic conditions in Brucellabroth (BBL) medium containing 10% inactivated horse serum for 24 hoursand then sprayed on M-BHM pylori agar medium containing 10% inactivatedhorse serum, to determine microbial eradication by detecting H. pylori.

In judgment of effectiveness of the medicines, the number of H. pyloribacteria detected in the stomach mucous membrane tissues of the sandrats given the combined medicine of 3 agents (this combined medicine isused in the method of eradicating the bacteria at present) is 0.001%(i.e. 1×10⁴ CFU/mL) relative to the original number of administeredbacteria (1×10⁹ CFU/mL), and thus a number identical to or less thanthis number of bacteria was regarded as effective. The results are shownin Table 11. TABLE 11 Effective number Medicine of animals (%) No. 23minocycline hydrochloride 5/5(100) CMC solution only none 0/5(0) Controlof combination 5/5(100) microbial eradication of the 3 agents

From the above result, the liquid preparation No. 23 in the presentinvention achieved the same level of microbial eradication as by therapywith combination of the 3 agents which is the present-day therapy ofmicrobial eradication.

The liquid preparation No. 23 gelled at the surface layer of the stomachmucous membrane by stomach acid, whereby minocycline hydrochloridecontained in the gel was protected against rapid hydrolysis by stomachacid, and a sufficient antibacterial effect was considered to beachieved by sustainedly releasing the medicine to the mucous membranesurface layer where H. pylori existed.

On the other hand, the administration of combination of 3 agents lead toreduction in H. pylori, but the amount of the combined 3 agentsadministered was very large. Therefore, there occurred a side effectthat congestion was observed in all regions of digestive tracts from thesmall to large intestines. Particularly, the duodenum was swollen withcongestion, and the gallbladder was enlarged. Further, possibly becauseof inhibition of stomach acid secretion by the proton pump inhibitor,the stomach was swollen significantly, and regions from the cardia tothe esophagus underwent reddish inflammation.

However, when the liquid preparation of the present invention wasadministered, such side effect did not occur.

EXAMPLE 12

200 mL of liquid preparation containing 750 mg amoxicillin and 200 mgclarithromycin, according to No. 1 in Example 10, was administered everyday before sleeping to each of 3 patients in their thirties to fiftieswho were judged to have gastritis by stomach endoscopic examination andjudged to be H. pylori positive by a biopsy sample culture test. Thisadministration was continued for 1 week. After the administration,whether H. pylori was present or absent was judged by an urearespiration test method. The results are shown in Table 12 below. TABLE12 Administration Antibacterial liquid preparation Before After Examineeadministration administration Examinee 1 present absent Examinee 2present absent Examinee 3 present absent

In the method of administering insurance-applicable 3 agents, that is,lansoprazole, amoxicillin and clarithromycin, 60 mg of lansoprazole,1,500 mg of amoxicillin and 400 mg of clarithromycin shall beadministered every day over 7 days. From the above result, it wasrevealed that lansoprazole as a proton pump inhibitor was not necessaryfor the oral liquid preparation of the present invention, and combineduse of the 2 antibiotics was sufficient, and half of the aboveadministration, that is, the daily dose of 750 mg amoxicillin and 200 mgclarithromycin indicated sufficient effect.

In addition, findings considered as side effects such as refluxesophagitis, diarrhea and taste abnormality, which are reported in theeradication of H. pylori, were not recognized in the examinees.Accordingly, the antibacterial agent consisting of the oral liquidpreparation of the present invention was considered unlikely to causeseverer side effects than before, and it was proved that the bacteriacan be removed while the daily life can be maintained.

EXAMPLE 13

The liquid preparations of the present invention having the compositionsin Tables 13 to 15 were prepared. TABLE 13 30 31 32 33 MedicinesCimetidine 0.4 g 0.2 g Pirenzepine 0.025 g Gefarnate 0.1 g Pectin 0.2 gGellan gum 0.05 g Sodium alginate 0.05 g Carrageenan 0.05 g 0.05 gTamarind seed gum 0.1 g Calcium carbonate 0.05 g 0.04 g 0.05 g Whitesoft sugar 1.5 g D-Sorbitol 2 g 2 g 1 g Distilled water balance balancebalance balance Total amount 10 g 10 g 10 g 10 g

TABLE 14 34 35 36 37 Medicines Urogastrone 0.024 g Azulene sulfonate Na0.445 g 0.99 g L-glutamine 0.0015 g 0.003 g Teprenone 0.05 g Pectin 0.2g 0.2 g 0.2 g Gellan gum 0.05 g 0.08 g Sodium alginate 0.05 g 0.05 gCarrageenan 0.05 g Tamarind seed gum 0.1 g Calcium carbonate 0.04 gWhite soft sugar 2 g D-Sorbitol 1 g 1 g 1.5 g Distilled water balancebalance balance balance Total amount 10 g 10 g 10 g 10 g

TABLE 15 38 39 40 41 Medicines Cetraxate HCl 0.2 g Sulpiride 0.2 g 0.1 gAlprostadil alfadex 0.0003 g Pectin 0.02 g 0.02 g 0.04 g Gellan gum 0.05g 0.05 g Sodium alginate 0.05 g Carrageenan 0.04 g Tamarind seed gum0.05 g 0.1 g Xanthane gum 0.01 g Calcium carbonate 0.04 g 0.05 g Whitesoft sugar 1 g 1 g 1.5 g D-Sorbitol 2 g Distilled water balance balancebalance balance Total amount 10 g 10 g 10 g 10 g

EXAMPLE 14 Test of Therapeutic Effect on a Rat as Acetic Acid ChronicUlcer Model

24 Wister male rats weighing about 200 g were divided into 8 groups andfasted overnight, and acetic acid ulcer was causeed in each rat. Thatis, the rats were anesthetized under Nembutal and the belly was cutalong the midline to remove the stomach. Then, a cylinder of 100 mm indiameter charged with absorbent cotton impregnated sufficiently with100% acetic acid was pressed against the border between the stomach andthe pyloric region for about 30 seconds, and the acetic acid adhering tothe serous membrane was wiped off with a germ-free gauze, and the bellywas sutured. After 6 weeks, one rat was picked up as the control atrandom from the untreated group, killed and dissected to confirm ulcerformation.

0.5 ml of cetraxate hydrochloride liquid preparation No. 38, thecimetidine liquid preparation No. 30 and the teprenone liquidpreparation No. 37, respectively, were administered daily once for 2weeks to the stomachs of 3 rats as liquid preparation administrationgroup. As the control, a purified aqueous solution of each medicine wasadministered to the 3 groups each consisting of 3 rats (positivecontrol), the liquid preparation consisting of the liquid matrix onlywas administered to one group of 3 rats (negative control), and purifiedwater only was administered to one group of 3 rats (untreated group).

In the seventh and eight weeks, one untreated rat selected at random waskilled and the belly was opened to reconfirm formation of stomach ulcer.Each rat was killed in the eight week and the area of the ulcer wasmeasured, and the ulcer coefficient was determined according to a methodof Okabe et al. (Okabe S, Roth J L A, Pfeitter C J: A method forexperimental penetrating gastric and duodenal ulcers in rats.Observation on normal healing. Amer J Dig Dis 16: 277-284, 1971). Theulcer coefficient was 1 for 1 to 10 mm², 2 for 11 to 20 mm², and 3 for21 to 30 mm². The results are shown in Table 16. TABLE 16 Average ulcerUlcer coefficient coefficient Untreated group 3 — — — No. 38 1 2 1 1.33Only liquid matrix Negative 3 2 3 2.67 control Cetraxate HCl solutionPositive 2 2 3 2.33 control No. 30 2 2 2 2 Cimetidine solution Positive3 3 2 2.67 control No. 37 2 2 1 1.67 Teprenone solution Positive 3 2 22.33 control

From the above results, it was proved that the liquid preparationaccording to the present invention exhibits therapeutic effect onstomach ulcer. Teprenone having tissue-repairing action or cetraxatehydrochloride having viscous fluid production/secretion promoting actionwere recognized to be more effective against stomach ulcer than byattach factor inhibiting type such as cimetidine.

On the other hand, even if the medicine solution was administereddirectly (positive control), effect of reducing ulcer was recognized.However, the effect was lower than that of the liquid preparation of thepresent invention.

Accordingly, it was proved that the liquid preparation of the presentinvention exhibits a higher therapeutic effect on ulcer than that of theconventional preparation.

EXAMPLE 15 Therapeutic Effect of Liquid Preparation in IndomethacinUlcer Rat Model

18 Wister male rats weighing about 200 g were divided into 4 groups,that is, an experimental group of 5 animals, control groups (a positivecontrol group of 5 animals and a negative control group of 5 groups),and an untreated group for confirming formation of ulcer. These ratswere fasted for 24 hours, and then indomethacin (IND) suspended in 1%carboxymethyl cellulose (CMS) solution was administered in a dose of 20mg/kg to the rats via an oral probe for rat into the stomach to induceindomethacin ulcer. In a preliminary test, the blood concentration ofindomethacin reached the maximum after 3 hours, and erosive bleeding wasobserved in the stomach.

3 hours after administration of indomethacin, prostaglandin (PGE1)liquid preparation No. 41 (containing alprostadil alfadex as themedicine), PGE1 solution dissolved in purified water in a dose of 3.3μg/kg in weight as a positive control, the liquid matrix only wasadministered as a negative control, and purified water only forconfirming formation of ulcer to the untreated group, respectively, wasadministered. After 1 hour, the rats were given feed. The untreatedgroup after 3 hours from administration of indomethacin and the othergroups after 24 hours were killed, and dissected to judge ulcer andbleeding in the stomach.

Indomethacin ulcer in the fasted rats is different from that in humans,and develops in the stomach without generating in the pyloric vestibule.Therefore, judgment was made on the basis of bleeding. That is, nobleeding was expressed as negative (−), trace bleeding was given (±),dotted bleeding (+), and broad bleeding (++). The results are shown inTable 17. TABLE 17 Administered preparation Judgment Untreated + + ++group Negative Liquid matrix only ++ ++ ++ control Positive PEG1solution ± + − ± ± control No. 41 PEG1-containing + ± ± − − liquidpreparation

It is known that in an indomethacin ulcer model using a fasted rat,bleeding erosion in the stomach is inhibited by H2 blocker, acidregulator, anti-choline agent, proton pump inhibitor, prostaglandinpreparation or mucous membrane protecting agent (Susumu Okabe,Experimental Model of Digestive Ulcer (in Japanese), Nippon Rinsho, 42:43-47, 1979). On the other hand, in the rat fasted for 24 hours and thenfed for only 1 hour, the lesion in the corpus ventriculi is inhibited,and similar to human ulcer, the ulcer develops in regions of the pyloricvestibule to the small intestine. It is also known that no preparationother than the prostaglandin preparation is effective against this ulcerin the pyloric vestibule (Satoh, H., et al., Gastroenterology, 81:719-725, 1981)).

From the above result, it was revealed that in the indomethacin ulcerrat fasted for 24 hours in this experiment, bleeding was ameliorated byadministering prostaglandin (PEG1) having a site protection effect onthe stomach mucous membrane.

However, it was revealed that the effect of PEG1 is higher whenadministered as the liquid preparation of the present invention than byadministering as it is. This suggests that the liquid matrix in theliquid preparation of the present invention gels with stomach acidthereby protecting the stomach mucous membrane physically andsustainedly releasing the medicine (EG1 in this example), whereby PEG1is utilized more effectively in the affected area to treat the ulcer.

PREPARATION EXAMPLE 1

Ingradients Blending quantity (mass %) Sodium alginate 0.5 Pectin 0.5Calcium carbonate 5.0 Methyl paraben 0.3 Distilled water suitable amount

PREPARATION EXAMPLE 2

Ingradients Blending quantity (mass %) Sodium alginate 0.5 Pectin 0.5Calcium carbonate 5.0 Distilled water suitable amount

PREPARATION EXAMPLE 3

Ingradients Blending quantity (mass %) Gellan gum 1.0 Arabic gum 1.0Distilled water suitable amount

PREPARATION EXAMPLE 4

Ingradients Blending quantity (mass %) κ-Carrageenan 0.5 Magnesium oxide5.0 Distilled water suitable amount

PREPARATION EXAMPLE 5

Ingradients Blending quantity (mass %) Sodium alginate 0.5 Pectin 0.5Sawacillin (Amoxicillin) 0.5 Calcium carbonate 5.0 Methyl paraben 0.3Distilled water suitable amount

PREPARATION EXAMPLE 6

Ingradients Blending quantity (mass %) Sodium polyacrylate 1.0 Aluminumhydroxide 5.0 Distilled water suitable amount

PREPARATION EXAMPLE 7

Ingradients Blending quantity (mass %) Gellan Gum 1.0 Amoxicillin 2.5Calcium carbonate 5.0 Glycerin 20.0 Preservative suitable amountDistilled water suitable amount

PREPARATION EXAMPLE 8

Ingradients Blending quantity (mass %) Cimetidine 2.0 Sodium alginate0.5 Pectin 0.5 Calcium carbonate 5.0 D-sorbitol 20.0 pH adjusting agent(hydrochloric acid) suitable amount Distilled water suitable amount

PREPARATION EXAMPLE 9

Ingradients Blending quantity (mass %) Diclofenac sodium 0.5 Sodiumalginate 0.5 Pectin 0.5 Calcium carbonate 5.0 Distilled water suitableamount

PREPARATION EXAMPLE 10

Ingradients Blending quantity (mass %) Theophylline 2.0 Sodium alginate0.5 Pectin 0.5 Calcium carbonate 5.0 Preservative suitable amountDistilled water suitable amount

PREPARATION EXAMPLE 11

Ingradients Blending quantity (mass %) Ketoprofen 2.0 Sodium alginate0.5 Pectin 0.5 Calcium carbonate 5.0 Propylene glycol 20.0 Distilledwater suitable amountExploitation in Industry

The liquid matrix of the present invention can easily solubilize,disperse or suspend medicine, is liquid to permit easy swallowing, iseasily and highly operative in sterilization, has effect of maskingbitter tastes of medicine and the like, and can gel in the living bodyto regulate the rate of release of the medicine. Accordingly, an oralliquid preparation containing medicine in the liquid matrix of thepresent invention can achieve nonconventional excellent sustainedrelease although it is liquid.

In particular, the oral liquid preparation mixed with efficacy componentshowing anti-H. pylori activity as the medicine gels by introducing itinto the stomach, and thus it protects the efficacy component unstableto acidic conditions and is disintegrated sustainedly to release theefficacy component, whereby the content of the efficacy componentcontained therein and the frequency of administration can be reduced,and side effects hardly occur.

In addition, the liquid preparation does not necessitate a proton pumpinhibitor and the like for inhibiting secretion of stomach acid, andthus there is no side effect of such medicine.

Unlike conventional anti-H. pylori preparations, the liquid preparationof the present invention applied to therapy for H. pylori infection hasa particularly excellent feature that proton pump inhibitors are notrequired, and thus it is extremely effective as a therapeutic agent forHelicobacter pylori infection.

The oral liquid preparation mixed with the medicine having therapeuticeffect on stomach ulcer or duodenal ulcer also shows sustained releaseof the medicine and exhibits a particularly high therapeutic effect.That is, the oral liquid preparation unlike the conventional anti-ulceragent, can sustainedly release the medicine directly to an affectedregion, and thus the effectiveness of the medicine is high, and sideeffects can be reduced.

Accordingly, the liquid preparation of the present invention used intherapy of stomach ulcer or duodenal ulcer can reduce its dose ascompared with the conventional anti-ulcer agent, and can thus exhibit ahigh therapeutic effect with less side effects, and is thus extremelyuseful.

1-24. (canceled)
 25. A liquid matrix which is a liquid assistant forfacilitating swallowing medicine comprising a water-soluble polymer,wherein the water-soluble polymer gellates under acidic conditions, andthe breaking stress of the gel is about 3.00×10² N/m² or more.
 26. Theliquid matrix according to claim 25, wherein the breaking stress of thegel is 2.00×10³ N/m² or more.
 27. The liquid matrix according to claim25, wherein the viscosity of the liquid matrix is 3.0×10⁻¹ Pa.s or less.28. The liquid matrix according to claim 25, comprising insoluble saltreleasing polyvalent metallic cation under acidic conditions.
 29. Theliquid matrix according to claim 28, wherein the insoluble salt isalkaline earth metal salt of inorganic acid.
 30. The liquid matrixaccording to claim 25, wherein the water-soluble polymer has carboxylgroup and/or sulfonic acid group in the chemical structure thereof. 31.The liquid matrix according to claim 25, wherein the water-solublepolymer is alginate.
 32. The liquid matrix according to claim 25,wherein the water-soluble polymer is pectin.
 33. The liquid matrixaccording to claim 25, wherein the water-soluble polymer is combinationof alginic acid and pectin.
 34. The liquid matrix according to claim 25,wherein the water-soluble polymer is a combination of alginate andpectin.
 35. The liquid matrix according to claim 25, wherein thewater-soluble polymer is gellan gum.
 36. The liquid matrix according toclaim 25, wherein the water-soluble polymer is combination of gellan gumand pectin.
 37. The liquid matrix according to claim 25, wherein theviscosity of the liquid matrix is about 1.0×10⁻¹ Pa.s or less.
 38. Anoral liquid preparation comprising the liquid matrix according to claim25 and medicine.
 39. The oral liquid preparation according to claim 38,wherein the medicine has anti-Helicobacter pylori activity.
 40. The oralliquid preparation according to claim 38, wherein the medicine is atleast one member selected from the group consisting of penicillinantibiotics, macrolide antibiotics, tetracycline antibiotics, cephamantibiotics, pyridonecarboxylic acid synthetic antibacterial agents andmetronidazole.
 41. The oral liquid preparation according to claim 40,wherein the medicine is at least one member selected from the groupconsisting of amoxicillin, clarithromycin, roxithromycin, minocyclinehydrochloride, cephaclor, cephalexin, ofloxacin, tosufloxacin tosylate,and levofloxacin.
 42. The oral liquid preparation according to claim 40,wherein the medicine is metronidazole.
 43. The oral liquid preparationaccording to claim 38, wherein the liquid matrix is gelled in thestomach thereby exhibiting sustained release of the medicine.
 44. Theoral liquid preparation according to claim 38, wherein the medicine hastherapeutic effect on stomach ulcer or duodenal ulcer.
 45. The oralliquid preparation according to claim 44, wherein the medicine havingtherapeutic effect on stomach ulcer or duodenal ulcer is of protectionfactor promoting type.
 46. The oral liquid preparation according toclaim 45, wherein the medicine having an effect of promoting protectionfactor and a therapeutic effect on stomach ulcer or duodenal ulcer isprostaglandin.
 47. The oral liquid preparation according to claim 44,wherein the liquid matrix is gelled in the stomach thereby exhibitingsustained release of the medicine.
 48. A method of utilizing an aqueoussolution of a water-soluble polymer gelling under acidic conditions as acomponent in a sustained-release oral liquid preparation.